1. Field of the Invention
The Anti-AIDS Amines (I) are useful in treating individuals who have AIDS as well as those individuals who are HIV positive but do not as yet have AIDS.
2. Description of the Related Art
An estimated one to one and one-half million people in the United States are infected with a human retrovirus, the human immunodeficiency virus type I (HIV-1) which is the etiological agent of acquired immunodeficiency syndrome, AIDS, see Science, 661-662 (1986). Of those infected, an estimated two hundred and fifty thousands people will develop AIDS in the next five years, see Science, 1352-1357 (1985). On Mar. 20, 1987, the FDA approved the use of the compound, AZT (zidovudine), to treat AIDS patients with a recent initial episode of pneumocystis carinii pneumonia, AIDS patients with conditions other than pneumocystis carinii pneumonia or patients infected with the virus with an absolute CD4 lymphocyte count of less than 200/mm.sup.3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
U.S. Pat. No. 4,724,232 claims a method of treating humans having acquired immunodeficiency syndrome utilizing 3'-azido-3'-deoxy-thymidine (azidothymidine, AZT).
Following the discovery of the anti-HIV activity of AZT, much effort has been focused on a wide variety of other dideoxynucleoside analogues in the search for superior agents. In the case of the 2',3'-dideoxy series, ddC and ddI have shown potent activity against HIV in vitro and have been evaluated in clinical trials, see Drug News & Perspectives, 5(3) 153-169 (1992) in particular page 160. The FDA has approved ddI for the treatment of HIV-1 infections in adults and pediatrics patients who are intolerant to, or whose health has significantly deteriorated while on, AZT treatment, see AIDS Research and Human Retroviruses, 8(6), 963-990, 1992 (1992) in particular page 966.
It is known in the art that certain antibiotics and polyanionic dyes inhibit retrovirus reverse transcriptase.
International Publication No. WO 88/08424 (U.S. Pat. No. 5,120,843) disclosed compounds which can be represented as aromatic-connector-piperazine-substituted aromatic! or aromatic-connector-piperazine-substituted heteroaromatic!, in particular see the compounds of formulas (I) and (III). None of those compounds were disclosed as having the utility set forth in this invention. In U.S. Pat. No. 5,120,843 it was disclosed that the compounds of formula (I) of International Publication No. WO 88/08424 were useful against AIDS.
Many publications have reported the ability of various sulfated compounds to inhibit virus replication, including HIV.
Nature 343, 470 (1990) and Science 250, 1411 (1990) discloses potent benzodiazepin type reverse transcriptase inhibitors. The compounds of the present invention are not benzodiazepin type compounds.
U.S. Pat. Nos. 3,146,234 and 3,188,313 disclose a number of compounds which can be represented as: EQU (5-substituted)-(indol-2-yl)-linker-piperazinyl-(substituted phenyl), EQU (5-substituted)-(indol-2-yl)-linker-piperazinyl-(unsubstituted heteroaryl).
The compounds of the present invention do not include phenyl (whether substituted or not) attached to the piperazinyl moiety. Further, the compounds of the present invention require that the heteroaryl group must be substituted.
VINITI, 3979-82 (1982) in Russian and Chem. Abst. 100(7) 51549b (1984) discloses a compound which can be represented as EQU 5-methoxy(indol-2-yl)-carbonyl-piperazinyl-(2-quinolinyl)
which differs from the claimed compounds in that none of the claimed compounds have quinoline structure or any bicyclic structure attached to the piperazinyl, piperidinyl or aminopiperidinyl moiety.
JP 01132579 (1987) discloses compounds which can be represented as EQU (optionally substituted)-indol-2-yl!-CO-piperazinyl-(CH.sub.2).sub.n -pyridinyl!
which have very strong blood platelet agglutination inhibiting activity where n is 1-5 which differs from the claimed compounds in that the claimed compounds do not permit any linking group between the piperazinyl moiety and the heteroaryl group.
Indian J. Chem. Sect. B, 17B(3), 246-9 (1979) and Indian J. Med. Res., 63(10), 1418-25 (1975) disclose compounds which can be represented as: EQU (indol-2-yl)-carbonyl-piperazinyl-(CH.sub.2).sub.n -(optionally substituted phenyl)
The Indian J. Chem. Sect. B, 17B(3), 246-9 (1979) reported on p. 247 that none of the compounds showed any noteworthy (CNS) biological activity. The Indian J. Med. Res., 63(10), 1418-25 (1975) reported some of the compounds they prepared had anti-viral activity against Semliki forest virus (SFV) in mice. One compound, a dihydroisoquinolin was tested and found to be inactive against new castle disease virus in chick embryo. These compounds differ from the claimed compounds in that the claimed compounds require a heteroaryl group not a phenyl group attached to the piperazinyl moiety.
International Publication EP 370 381 A2, published 5 May 90 discloses compounds which can be represented as EQU heteroaryl!-CO-piperazinyl-quinolinone!
where heteroaryl includes 2-indolyl which differ from the claimed compounds in that none of the claimed compounds have quinoline structure or any bicyclic structure attached to the piperazinyl moiety. The disclosed compounds possess cardiotonic and hypotensive activities and the capability of reducing the heart rate.
J. Med. Pharm. Chem., 5, 932-43 (1962) and U.S. Pat. No. 3,135,794 disclose CAS 100731-59-7 which can be represented as: EQU 5,6-dimethoxy-(indol-3-yl)-ethylene-piperazinyl-(2-pyridinyl)
The compounds of the present invention do not include 3-indolyl type compounds nor to they include compounds where the "linker" is ethylene. Further, they require that the heteroaryl group (pyridinyl) be substituted.
U.S. Pat. No. 4,954,502 (Example 38) discloses a compound which can be represented as: EQU 5-methoxy-(indol-3-yl)-ethylene-piperazinyl-(3-methoxypyridin-2-yl)
The compounds of the present invention do not include 3-indolyl type compounds nor to they include compounds where the "linker" is ethylene. While they require that the heteroaryl group (pyridinyl) be substituted methoxy and other alkoxy substitution is prohibited.
Other 3-indolyl compounds not believed to be as relevant as the ones cited above are disclosed in U.S. Pat. No. 3,751,417, J. Org. Chem., 44(26), 4809-13 (1979), U.S. Pat. No. 4,302,589, U.S. Pat. No. 3,328,407, FR 1,551,082, Arch. Pharm. (Weinheim, Ger.), 321(7), 377-83 (1988) and J. Med. Chem., 9(1), 140-2 (1966).
U.S. Pat. Nos. 5,032,598 and 5,215,989 discloses class III anti-arrhythmic compounds of the formula EQU R.sup.2 R.sup.3 Ar--B!--X--Q--Y--R.sup.1
which if the appropriate substituents were selected generically encompasses some of the compounds of the present invention.
U.S. Pat. Nos. 3,472,855 and 3,562,278 disclose 3-indolinyl compounds which are useful as psychomotor depressants. The Anti-AIDS Amines (I) of the present invention are 2-indolyl not 3-indolyl compounds and are useful for a totally different purpose, inhibition of HIV-RT and treatment of AIDS.
U.S. Pat. No. 3,362,956 discloses compounds of the general formula EQU 3-quinolyl!-(CH.sub.2).sub.n -piperazinyl type!-pyridinyl/phenyl!.
The Anti-AIDS Amines (I) of the present invention differ from the prior art compounds in that they do not include 3-quinolyl type compounds.
U.S. Pat. No. 3,472,854 discloses compounds of the general formula EQU 2-benzimidazolyl!-(CH.sub.2).sub.n -piperazinyl type!-pyridinyl/phenyl!.
The Anti-AIDS Amines (I) of the present invention differ from the prior art compounds in that no methylene linker is permitted between the benzimidazolyl group and the piperazinyl group.
U.S. Pat. No. 3,491,098 discloses compounds of the general formula EQU 4(5)-imidazolyl!-(CH.sub.2).sub.n -piperazinyl type!-pyridinyl/phenyl!.
The Anti-AIDS Amines (I) of the present invention differ from the prior art compounds in that no methylene linker is permitted between the imidazolyl group and the piperazinyl group.
U.S. Pat. No. 3,511,841 discloses compounds of the general formula EQU azaindolyl!-(CH.sub.2).sub.n -piperazinyl type!-pyridinyl/phenyl! EQU azaindolyl!-CO-piperazinyl type!-pyridinyl/phenyl!
The Anti-AIDS Amines (I) of the present invention differ from the prior art compounds in that they have substituted oxygen or substituted amino groups on the pyridinyl group.
International Publication No. WO 91/09849 discloses diaromatic substituted heterocyclic compounds of the type aryl/heteroaryl!-connector-piperazine type-aryl/heteroaryl useful in treating individuals infected with the HIV virus. This document discloses compounds of the type (substituted)indole-CO-piperazinyl-(non-alkyl substituted)pyridinyl.
International Publication No. WO 93/01181 also discloses compounds of the type (substituted)indole-CO-piperazinyl-(non-alkyl substituted)pyridinyl useful in treating individuals infected with the HIV virus.
EP 0 154 969 and U.S. Pat. No. 4,613,598 disclose compounds of the formula EQU substituted!-aromatic-CO--(CH.sub.2).sub.3-5 -piperazinyl!-Ar EQU substituted!-aromatic-CHOH--(CH.sub.2).sub.3-5 -piperazinyl!-Ar
where Ar is pyridinyl, --.phi. or substituted --.phi. which have the ability to lower blood pressure.
Proceedings of the National Academy of Sciences 88, 8806-10 (1991) discloses various bis(heteroaryl)piperazinyl non-nucleoside reverse transcriptase inhibitors which potently and specifically block human immunodeficiency virus type 1 replication.
There are a number of other chemically unrelated compounds which have been reported to inhibit HIV and/or be useful in the treatment of AIDS.